Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:4]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[CH:5][C:6]([CH3:14])=[C:7]([CH:13]=1)[O:8][CH2:9][C:10]([OH:12])=[O:11].B(Br)(Br)Br.OS(O)(=O)=O>C(Cl)Cl.CO.CCOC(C)=O>[OH:2][C:3]1[C:4]([S:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)=[CH:5][C:6]([CH3:14])=[C:7]([CH:13]=1)[O:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: BrB(Br)Br
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(O)cc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
A solution of [5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid, prepared according to Example 4, (1.0 g, 2.2 mmol) in 75 mL DCM at 0° C., was treated with dropwise addition of BBr3 (5.5 mL of a 1.0 M solution in DCM). After 30 minutes, the reaction was carefully quenched with 50% NH4OH. The reaction was then acidified to pH 1 with conc. HCl, and extracted with EtOAC. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then taken up in MeOH, followed by addition of 50 μL H2SO4, and then refluxing for 3 hours. The reaction was then diluted with EtOAc, washed 1×50 mL water, dried (Na2SO4), and the reaction concentrated in vacuo. The resulting ester was purified by recrystallization from EtOAC/Hexanes. The ester was then saponified in the same manner as described for Example 1, to give the title compound in 37% overall yield. IR cm−1:3408, 1752, 1323; 400 MHz 1H NMR (DMSO-d6) δ 9.56 (s, 1H), 7.82 (d, 2H, J=8.4 Hz), 7.74 (d, 2H, J=8.4 Hz), 7.31 (d, 2H, J=8.4 Hz), 6.92 (s, 1H), 6.30 (s, 1H), 4.55 (s, 2H), 4.00 (s, 2H), 1.95 (s, 3H). Anal. Calc'd for C23H19F3NO4S.0.1 H2O C, 61.35; H, 4.30. found: C, 61.08; H, 3.92.
Reaction SMILES: [CH:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH2:9][OH:10])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.O>CS(C)=O>[CH:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH:9]=[O:10])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(CCCCc1ccccc1)C(=O)N1CCC[C@H]1CO
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C(CCCCc1ccccc1)C(=O)N1CCC[C@H]1C=O
Reaction time: 0.17 h

Procedure:
N-(2-isopropyl-6-phenylhexanoyl)-L-prolinol was dissolved in dry DMSO (1.5 ml). Triethylamine (0.35 ml) was added to this solution. A solution of sulfur trioxide-pyridine complex (414 mg) in DMSO (1 ml) was dropped to this solution. The solution was stirred for 10 mins and poured into water. The mixture was extracted with ethyl acetate. The oily layer was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrocarbonate, followed by saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel to give the title compound (150 mg) having the following physical data:
Reaction SMILES: [H-].[CH:2]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:15][O:14][CH:2]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: OC1CCCCCCCCCCC1
Agent: [H-]
Product: c1ccc(COC2CCCCCCCCCCC2)cc1
Temperature: 125 °C

Procedure:
The hydride was mixed, under an argon atmosphere and by mechanical stirring, with cyclododecanol (130.0 g. 0.71 mol) and benzyl chloride (650.0 g, 5.14 mol). The reaction mixture was heated to 125° C. The mixture became very viscous when the temperature reached between 60° and 70° C. A mild exotherm was observed at about 100° C. which resulted in a marked viscosity decrease. If an efficient reflux condenser is not used, some external cooling may be necessary during the mild exotherm. The internal flask temperature increased to about 120° C. over ten minutes. The reaction flask was heated at 120° to 125° C. for an additional hour and then it was cooled to 25° C. The excess hydride was carefully destroyed by the addition of 100 mL of 95% ethanol under an argon atmosphere. The mixture was treated with 500 mL of aqueous saturated sodium chloride solution and extracted with three 400 mL portions of hexane. The organic layer was collected, washed with two 100 mL portions of water and two 100 mL portions of aqueous sodium chloride solution. The product mixture was dried over magnesium sulfate, filtered, and concentrated at 50° C. and 15 mm. The product was distilled at 144°-146° C./0.2 mm to give (180.7 g) 93.0% of the theoretical yield. Gas chromatography ("GC") showed that the product was 99% of a single component, IR (neat, cm-1) 2930, 2865, 1475, 1455, 1095 (C-O-C), 1070, 740; 13C NMR (ppm CDC13) 139.31, 128.17, 127.54, 127.21, 76.26 (α-ring carbon), 70.22 (α-chain carbon), 28.91, 24.75, 24.31, 23.30, 23.19, 20.81; MS, m/z (relative intensity) 274 (M+, 1.5), 245(0.1), 230(0.4), 183(8.2), 174(0.9),160(1.0), 145(0.8), 133(2.3), 118(2.7), 104(10.4), 91(100), 81(3.2), 65(12.7), 56(2.1). Anal calcd for C19H30O:C,83.15;H,11.02. Found: C,83.33;H,11.18.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[ClH:13].[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[C:22]2[NH2:25])=[CH:17][CH:16]=1>ClCCl>[ClH:13].[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[C:22]2[NH:25][C:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH3:12])=[NH:11])=[CH:17][CH:16]=1
Reactant: CCc1cccc(N(C)C#N)c1
Reactant: Nc1cccc2ccc(F)cc12
Agent: Cl
Solvent: ClCCl
Product: CCc1cccc(N(C)C(=N)Nc2cccc3ccc(F)cc23)c1
Temperature: 160 °C
Yield: 53.1 %

Procedure:
A mixture of N-(m-ethylphenyl)-N-methylcyanamide (195 mg, 1.21 mmol) and 7-fluoro-1-aminonaphthalene hydrochloride (200 mg, 1.01 mmol) was heated in a pre-heated oil bath at 160° C. for 2.5 hours and then al 1 owed to cool to room temperature. The resulting solid was taken up in dichloromethane and washed with 5% NaOH solution. The organic layer was concentrated and the resulting residue was treated at room temperature with 0.5M methanol-HCl solution (10 ml). It was concentrated and the resulting purple glass was purified by flash chromatography on silica gel to give N-(7-fluoro-1-naphthyl)-N'-(m-ethylphenyl)-N'-methylguanidine hydrochloride (192 mg, 53%) as off-white crystals. M.p.: 187°-90° C. IR (CHCl3): 1630, 3400 cm-1. 1H NMR (CD3Cl3): δ1.259 (t, 3H, J=7.9 Hz), 2.431 (q, 2H, J=7.9 Hz), 3.564 (s, 3H), 6.76-7.94 (m, 1OH). Anal. Calcd for C20H21N3FCl: C, 67.12; H, 5.92; N, 11.74. Found: C, 67.28; H, 6.00; N, 11.87.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:10]([C:12]([O:14]C(OCC)C)=[O:13])[OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CS(Cl)(=O)=O.[CH2:43]1[CH2:47][O:46][CH2:45][CH2:44]1>CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]1[O:13][C:12](=[O:14])[CH:10]([O:11][CH:45]([O:46][CH2:47][CH3:43])[CH3:44])[C:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: CCOC(C)OC(=O)C(O)C(NC(=O)OC(C)(C)C)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(C)OC1C(=O)OC(OC(C)(C)C)=NC1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a solution of 497 mg (1.16 mmol) of N-tertbutoxycarbonyl-O-(1-ethoxyethyl)-3,3-diphenylisoserine (3) in 20 mL of THF is added 261 mg (2.33 mmol) of solid potassium tert-butoxide and the mixture is stirred at 25° C. for 30 min. A solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 mL of THF is added and the mixture is stirred at 25° C. for 1.5 hour. The mixture is diluted with 80 mL of hexane and ethyl acetate, and this solution is extracted with 20 mL of saturated aqueous sodium bicarbonate solution and 10 mL of brine. The organic phase is dried over sodium sulfate and concentrated to give 243 mg (59%) of 2-tertbutoxy-4,4-diphenyl-5-(1-ethoxyethoxy)-4,5-dihydro-1,3-oxazin-6-one as a colorless oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[C:30]([CH3:38])[C:15]=1[C:16]([C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][N:21]=[CH:20][C:19]=1[O:28][CH3:29])=[O:17]>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[C:30]([CH3:38])[C:15]=1[C:16]([C:18]1[C:23]([C:24]([F:27])([F:25])[F:26])=[CH:22][N+:21]([O-:9])=[CH:20][C:19]=1[O:28][CH3:29])=[O:17]
Reactant: COc1cc(C)c(C(=O)c2c(OC)cncc2C(F)(F)F)c(OC)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(C)c(C(=O)c2c(OC)c[n+]([O-])cc2C(F)(F)F)c(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
6.1 g (28 mmol) of m-chloroperbenzoic acid (m-CPBA) was added at 0° C. to a chloroform 100 ml solution of 5.6 g (15 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine (Compound No. 122), followed by stirring at room temperature for 18 hours. The reaction solution was washed with a sodium hydroxide aqueous solution, and the solvent was distilled off under reduced pressure to obtain 5.8 g (yield: 99%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine-N-oxide (melting point 128 to 134° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH3:12].C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[CH2:12][Br:20]
Reactant: Cc1c(Br)cccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(Br)c1CBr
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 1-bromo-2-methyl-3-(trifluoromethyl)benzene (CXXVII) (5.7 g, 23.86 mmol) in CCl4 (50 mL) was added NBS (4.24 g, 23.86 mmol) and a catalytic amount of benzoyl peroxide. The reaction mixture was gently refluxed for 1 h. The reaction mixture was cooled to room temperature and the precipitate was removed by filtration. The solution was concentrated under reduced pressure and the crude product was dissolved in hexane and additional precipitate was removed by filtration. The filtrate was concentrated to dryness to give 1-bromo-2-(bromomethyl)-3-(trifluoromethyl)benzene (CXXVIII) as an orange oil (7.51 g, 23.62 mmol). 1H NMR (DMSO-d6) δ ppm 4.73 (s, 2H), 7.4 (dd, J=8 Hz, J=8 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 8.02 (d, J=8 Hz, 1H); 19F NMR (DMSO-d6) δ ppm −57.85 (s, 3F). The crude product was used without further purification for step 2.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6]([F:16])[C:5]([F:17])=[C:4]([F:18])[C:3]=1[F:19].[CH3:20]C(OC(C)=O)=O.C(OCC)(OCC)OCC.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[F:1][C:2]1[C:3]([F:19])=[C:4]([F:18])[C:5]([F:17])=[C:6]([F:16])[C:7]=1[C:8]([C:10](=[CH:20][NH:40][CH:37]1[CH2:39][CH2:38]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]
Reactant: NC1CC1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1F
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(F)c(F)c(F)c1F
Reaction time: 1.5 h
Yield: 108.1 %

Procedure:
A stirred solution of ethyl (pentafluorobenzoyl)acetate 1 (5.77 g, 20 mmol), Ac2O (8.02 mL, 8.34 g, 80 mmol) and triethyl orthoformate (5.1 mL, 4.54 g, 30 mmol) was heated at 130° C. for 1.5 h. The mixture was concentrated in vacuo and dried under high vacuum for 3 hours. The crude product 2 was dissolved in anhydrous CH2Cl2 (10 mL) and cyclopropyl amine (2.15 mL, 1.75 g, 30 mmol) was added very slowly at room temperature. After 1.5 h, the solvent was removed by evaporation to yield 3 as a dark yellow solid (7.55 g crude, quantitative) that was used in the next step without further purification.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11](=[O:14])([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=C.C(OCC)(=O)C>CC(C)=O>[CH2:11]([O:14][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH3:2])=[CH:10][CH:9]=1)[CH:17]=[CH2:18]
Reactant: C=CCBr
Reactant: O=C([O-])[O-]
Reactant: O=C(CO)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(C(C)=O)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
2-Hydroxyacetophenone (1.36 g, 10.0 mmol) was dissolved in acetone (50 mL). The resultant mixture was added with potassium carbonate (2.76 g, 20.0 mmol) and allylbromide (1.27 mL, 15.0 mmol) at room temperature and heated to reflux for 3 hours. The reaction solution was cooled to room temperature, added with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (n-hexane/ethyl acetate=10/1). 1-(4-(Allyloxy)phenyl)ethanone (1.76 g, 100%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:15]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)(=[O:17])[CH3:16].N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[C:15]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1)(=[O:17])[CH3:16]
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)C=CC#N)cc2)cc1

Procedure:
To a dispersion of 3.6 grams (0.017 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile and 4.7 g (0.02 mol) of 4-acetamidobenzenesulfonyl chloride in 50 ml of chloroform is added 2 ml of pyridine. There is an exothermic reaction and an upper yellow, oily layer is formed. After 48 hours at room temperature 50 ml of chloroform are added, followed by water. The water and chloroform layers are separated and discarded, and the oily layer is shaken with water, separated and then dissolved in 30 ml ethanol. After cooling, crystals are recovered having a melting point of 204°-205° C and consisting of 3-[4-(4-ACETAMIDOBENZENESULFONAMIDO)BENZENESULFONYL]acrylonitrile: ##SPC35##
Reaction SMILES: C(O[CH:4]([O:18]CC)[C:5](=O)[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH3:16])\[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])C.[OH-].[Na+].[C:23]([OH:26])(=O)[CH3:24].[BH4-].[Na+]>O1CCCC1>[OH:18][CH2:4]/[C:5](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH3:16])\[CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:8])=[CH:24]/[CH2:23][OH:26]
Reactant: CC(=O)O
Reactant: CCOC(OCC)C(=O)CC/C=C(/C)CCC=C(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C\CC/C(=C\CC/C(C)=C/CO)CO
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In 125 ml of anhydrous tetrahydrofuran was suspended 18 g of (E)-4-methyl-6-acetoxy-4-hexen-1-yltriphenylphosphonium iodide, and to this suspension was added dropwise two molar equivalents of a n-butyllithium-hexane solution at -20° C. in a stream of nitrogen. The resulting mixture was stirred at -20° C. for one hour and to this was further added 8.4 g of (Z)-1,1-diethoxy-6,10-dimethyl-5,9-undecadien-2-one (prepared in Referential example 3) in 25 ml of anhydrous tetrahydrofuran. The mixture was then stirred at room temperature for 3 hours and, after addition of ice water, extracted with n-hexane, and from the extract was obtained an oil. The oil was treated with a sodium hydroxide solution and acetic acid and reduced with 150 mg of sodium borohydride in the same manner as in Example 13, yielding 3.0 g of a mixture of the (E,Z,Z) and (E,E,Z) isomers.
Reaction SMILES: Cl.O[CH2:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>CN(C=O)C>[C:24]([O:23][C:21]([N:9]1[CH2:8][CH:7]([OH:10])[CH2:6][CH2:5][CH:4]1[CH3:3])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: OCc1ccc(O)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCC(O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.5 %

Procedure:
1.50 g (9.28 mmol) of 6-Hydroxymethyl-pyridin-3-ol hydrochlorid was hydrogenated under the conditions described in intermediate 63B. The crude product was dissolved in 5 ml DMF, 5.60 ml (32.00 mmol) of Hunig's base and 3.56 g (16.00 mmol) of BOC2O were added and the yellow solution was stirred 18 h at RT. Evaporation, extraction (AcOEt/water/brine) and chromatography (silica gel, AcOEt/MeOH) gave 0.35 g (15%) (rac)-5-hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl ester; MS: 216.4 (MH+)
Reaction SMILES: C[C:2]1[CH2:7][CH2:6][CH2:5][C:4](C)(C)[C:3]=1/[CH:10]=[CH:11]/C(/C)=C/C=C/C(/C)=C/C(O)=O.C1(CC(O)[C:31]([OH:33])=[O:32])C=CC=CC=1.CC(C)=[O:37]>>[C:3]1([C:10]([CH3:11])([OH:37])[C:31]([OH:33])=[O:32])[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C(O)Cc1ccccc1
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Reactant: CC(C)=O
Product: CC(O)(C(=O)O)c1ccccc1

Procedure:
Retinoyl phenyl lactic acid 0.5 gm which is synthesized from all-trans-retinoic acid and beta-phenyl lactic acid, according to a modified method described in Example 1, is dissolved in 5 ml of acetone, and the solution admixed with 95 gm of hydrophilic ointment, USP. The mixing is continued until a uniform consistency is obtained.
Reaction SMILES: [Cl:1][CH2:2]C(CCl)=O.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:26]([OH:28])=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[BH4-].[Na+].CCCCCC>CO.O1CCCC1>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:26]([OH:28])[CH2:2][Cl:1])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
To a solution of 0.226 mol of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of 807 mL of methanol and 807 mL of tetrahydrofuran at −2° C., is added 1.54 equiv. of solid sodium borohydride over one hundred minutes. The solvents are then removed under reduced pressure at 40° C. and the residue is dissolved in ethyl acetate (approx. 1 L). The solution is washed sequentially with 1M potassium hydrogen sulfate, saturated sodium bicarbonate and is then saturated sodium chloride solutions. After drying over anhydrous magnesium sulfate and filtering, the solution is removed under reduced pressure. To the. resulting oil is added hexane (approx. 1 L) and the mixture is warmed to 60° C. with swirling. After cooling to room temperature, the solids are collected and washed with 2 L of hexane. The resulting solid is recrystallized from hot ethyl acetate and hexane to afford 32.3 g (43% yield) of N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp 150-151° C. and M+Li+=340.
Reaction SMILES: [CH2:1]([Br:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>CC(C)=O>[Br-:8].[CH2:1]([N+:15]1[CH:16]=[CH:17][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccncc1
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: CC(C)c1cc[n+](Cc2ccccc2)cc1
Product: [Br-]
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Add benzyl bromide (4.3 mL, 36.4 mmol) to a solution of 4-isopropylpyridine (4.8 mL, 36.4 mmol) in acetone (16.3 mL). Stir the reaction mixture at 55° C. overnight. Concentrate the solvent and add diethyl ether. Sonicate the mixture and then decant the solvent. Dry the solid under vacuum to obtain the title compound as a pale yellow waxy solid (11.1 g, 100%). MS (m/z): 212 (M-Br).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=O.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)(=[O:29])=[O:28].C(N(CC)C(C)C)(C)C>C(O)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][CH:5]=[C:4]([NH:36][CH:33]2[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1ccccc1C(=O)c1ccc(Cl)nc1N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C(=O)c1ccc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Temperature: 170 °C
Yield: 58.7 %

Procedure:
A mixture of (2-Amino-6-chloro-pyridin-3-yl)-(2-methoxy-phenyl)-methanone (24.9 mg, 0.0948 mmol, Example 5), 1-methanesulfonyl-piperidin-4-ylamine (50.6 mg, 0.284 mmol, from Step A above), N,N-diisopropylethylamine (38mg, 0.294 mmol) and ethanol (2.7 mL) were heated at 160-180° C. in a sealed tube under microwave conditions for 0.5-4 hrs. The resulting reaction mixture was concentrated in vacuo and the residue was purified on silica gel with methylene chloride/methanol to give [2-Amino-6-(1-methanesulfonyl-piperidin4-ylamino)-pyridin-3-yl]-(2-methoxy-phenyl)-methanone as a white solid (22.5 mg, 58% yield). HRMS, observed: 405.1594, calcd for (M+H)+: 405.1591.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](F)=[C:6]([F:14])[C:5]=1[F:15]>C1COCC1>[F:14][C:6]1[C:5]([F:15])=[C:4]([F:3])[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]=1[NH:2][CH3:1]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1F
Reactant: CN
Solvent: C1CCOC1
Product: CNc1c([N+](=O)[O-])cc(F)c(F)c1F
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
A solution of MeNH2 in THF (50.7 mL, 2 M, 101 mmol) was added dropwise to a solution of 1,2,3,4-tetrafluoro-5-nitrobenzene (9.88 g, 50.7 mmol) in THF (200 mL) at −20° C. The mixture was stirred at −20° C. for 1.5 h, concentrated, washed with brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. Crystallization from EtOAc/PE gave the sub-title compound. Yield: 8.5 g (81%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:32][CH2:31][C:5]2([CH2:9][N:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23](F)=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2].[NH3:33]>CN(C=O)C>[NH2:33][C:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][N:8]3[CH2:7][CH2:6][C:5]4([CH2:31][CH2:32][N:3]([CH2:1][CH3:2])[CH2:4]4)[CH2:9]3)=[CH:17][CH:16]=2)=[O:30])=[CH:21][C:22]=1[N+:27]([O-:29])=[O:28]
Reactant: N
Reactant: CCN1CCC2(CCN(CCc3ccc(NC(=O)c4ccc(F)c([N+](=O)[O-])c4)cc3)C2)C1
Solvent: CN(C)C=O
Product: CCN1CCC2(CCN(CCc3ccc(NC(=O)c4ccc(N)c([N+](=O)[O-])c4)cc3)C2)C1
Reaction time: 8 h

Procedure:
N-{4-[2-(7-Ethyl-2,7-diaza-spiro[4.4]non-2-yl)-ethyl]-phenyl}-4-fluoro-3-nitro-benzamide from above was dissolved in DMF (15 ml) and the solution was cooled in an ice bath and saturated with ammonia gas for 10 min. The flask was sealed and left at room temperature overnight. The DMF was then evaporated under reduced pressure and the residue partitioned between dichloromethane and 0.1 N KOH. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on silica gel using 10% MeOH/CH2Cl2 1% TEA to afford 4-Amino-N-{4-[2-(7-ethyl-2,7-diaza-spiro[4.4]non-2-yl)-ethyl]-phenyl}-3-nitro-benzamide (996 mg) as a yellow foam which was used as is in the next step. 1H NMR (300 MHz, d6-DMSO) δ 10.2 (s, 1H), 8.70 (s, 1H), 7.96 (d, 1H), 7.82 (s, 2H), 7.63 (dd, 2H), 7.24 (dd, 2H), 7.10 (d, 1H), 2.65-2.35 (m, 14H), 1.96 (m, 4H), 1.23 (t, 3H).